The long-term aim of this work is to define the loci and mechanisms of cytogenetic variation in somatic cells, including the relation of such changes in neoplastic conversion. Our studies in mitochondrial genetics are designed to explore segregation, linkage, and recombination of cytoplasmic determinants in cultures of Chinese hamster cells. Models for experimental analysis are based on resistance to antimycin A, chloramphenicol, and other antimitochondrial drugs. Localization of these putative mitochondrial markers will be sought by fusing isolated mitochondria from resistant to sensitive cells, and by DNA transformation. Our program also deals with sequential variations in long-term culture as possible analogues of the multistage transitions that occur in carcinogenesis. Work we have completed with bromodoxyuridine suggests that resistance to this drug arises by spontaneous mutation which facilitates a continuing process of drug-induced changes. To see if this concept has a more general significance we plan to analyze the development of resistance by Chinese hamster cells to fluoride and the chromate in long-term culture. Studies are to be made on mechanisms of resistance, kinetics of variation, and the importance of induction and spontaneous mutation in population changes. These data will be used to design experiments with mouse cells on mechanisms of metal carcinogenesis. A non-tumorigenic line of mouse cells will be exposed to chromate in culture, and variations appearing in vitro will be assayed for neoplastic conversion by animal injection. Tumors will also be induced directly in mice by implantation of calcium chromate. The properties of these cells will be compared to those of populations exposed to chromate in culture only.